Predrag Novak

Dioxomolybdenum(VI) and dioxotungsten(VI) complexes chelated with the ONO tridentate hydrazone ligand: synthesis, structure and catalytic epoxidation activity

Synthesis of the dioxomolybdenum(VI) complexes [MoO2(L3OMe)(EtOH)] (1), [MoO2(L4OMe)(EtOH)] (2) and [MoO2(LH)(EtOH)] (3) and dioxotungsten(VI) complexes [WO2(L3OMe)(EtOH)] (4), [WO2(L4OMe)(EtOH)] (5) and [WO2(LH)]n (6a) was carried out using [MO2(C5H7O2)2] (M = Mo or W) and the corresponding aroylhydrazone ligand H2LR (3-methoxysalicylaldehyde 4-hydroxybenzhydrazone (H2L3OMe), 4-methoxysalicylaldehyde 4-hydroxybenzhydrazone (H2L4OMe), or salicylaldehyde 4-hydroxybenzhydrazone (H2LH) in ethanol. Compounds obtained upon heating of the mononuclear complexes in acetonitrile or dichloromethane, [MO2(LR)]n (1a–6a) or [MoO2(L3OMe)]2 (1b), respectively, were also investigated. Crystal and molecular structures of the mononuclear 1, 2 and 3, polynuclear 1a·MeCN and dinuclear 1b complexes were determined by the single crystal X-ray diffraction method. Powder X-ray diffraction showed isostructurality of 1 and 4, and 2 and 5. The complexes were further characterized by elemental analysis, IR spectroscopy, TG and DSC analyses, and one- and two-dimensional NMR spectroscopy. The catalytic performances of 1–5 and 6a were investigated for epoxidation of cyclooctene using aqueous tert-butyl hydroperoxide (TBHP) as the oxidant.

LC―NMR and LC―MS identification of an impurity in a novel antifungal drug icofungipen

Successful use of LC-NMR and LC-MS for rapid identification of an impurity in a novel antifungal drug icofungipen has been demonstrated. Complementary information obtained from the two methods made it possible to determine the structure of A1 prior to its isolation and purification. Stop-flow LC-NMR ((1)H and DQFCOSY), LC-MS and LC-MS/MS spectra have shown that A1 is structurally related to icofungipen. It was later isolated and prepared synthetically and its structure was corroborated by high-resolution NMR spectroscopy.

Investigation of hydrogen bond structure in benzoic acid solutions

Abstract Significant changes in 13 C chemical shifts of benzoic acid (BA) were observed for the carboxyl and quarternary carbon atoms on going from non-polar benzene to solvents with different hydrogen bond donor or acceptor abilities. Shielding effects of 6.145 and 5.413 ppm at the carboxyl carbon in dimethyl sulfoxide (DMSO) and acetone, respectively, are due to the redistribution of electron density upon the formation of new intermolecular hydrogen bonds with solvent molecules. 1 H NMR upfield shifts of the carboxyl proton in DMSO and chloroform solutions in comparison with benzene solution, and shifts in the CO stretching frequency, ν CO , observed in infrared spectra of BA complexes are consistent with these results. Structural parameters and interaction energies of the hydrogen-bonded complexes determined by quantum-chemical calculations substantiate the experimental observations. Using the semiempirical PM3 hamiltonian, hydrogen bonding was treated as the donor-acceptor mechanism within the natural bond orbital (NBO) formalism. Two correlations, which reflect hydrogen bonding in different solvents, are proposed: one between the 13 C chemical shifts and the change in p-character of the carboxyl carbon atom and the other between the carboxyl CO stretching frequency and the calculated interaction energy of the hydrogen-bonded complexes.

Pyridoxal hydrazonato molybdenum(VI) complexes: assembly, structure and epoxidation (pre)catalyst testing under solvent-free conditions

Pyridoxal hydrazonato molybdenum(VI) complexes were prepared by the reaction of the corresponding hydrazone (H2L1 = pyridoxal isonicotinic acid hydrazone, H2L2 = pyridoxal benzhydrazone, H2L3 = pyridoxal 4-hydroxy benzhydrazone) and [MoO2(acac)2] under appropriate conditions. The complexes can be classified into three categories: mononuclear [MoO2(L1–3)(MeOH)], polynuclear [MoO2(L1–3)]n and hybrid organic–inorganic compounds with the Lindqvist polyoxomolybdate [MoO2(HL1–3)]2Mo6O19. A unique example of a cationic polymer assembly with Lindqvist anions is reported herein for the first time. The compounds were characterised by elemental, TG and DSC analyses and by spectroscopic (IR, UV-Vis, 1H, 13C NMR) techniques. The crystal and molecular structure of the pyridoxal benzhydrazone H2L2, three mononuclear complexes [MoO2(L1–3)(MeOH)], and the Lindqvist-containing compounds [MoO2(HL2)]2Mo6O19·2MeCN and (H4L1)Mo6O19 were determined by single crystal X-ray diffraction. All complexes were tested as (pre)catalysts for the epoxidation of cyclooctene under solvent-free conditions with the use of aqueous TBHP (TBHP = tert-butylhydroperoxyde) as an oxidant. Optimal results in terms of conversion, selectivity, TOF and TON were obtained at very low (pre)catalyst loadings (0.05% [Mo] vs. substrate). The influence of the Linqvist anion on catalytic performance is discussed.

Probing the Interactions of Macrolide Antibiotics with Membrane- Mimetics by NMR Spectroscopy

Interactions of macrolide antibiotics with biological membranes contribute to their bioavailability but are also involved in the formation of phospholipidosis, which is caused by the inhibition of phospholipase A(1) activity. We determined the interaction strength and localization of macrolide antibiotics with membrane-mimetics. Macrolides bind to membrane-mimetics with the positively charged amino groups being close to the micelle surface and thereby protect the lipids from being degraded by phospholipase A(1) rather than inhibiting the enzyme.

Free and bound state structures of 6-O-methyl homoerythromycins and epitope mapping of their interactions with ribosomes.

The solution and solid state conformations of several 6-O-methyl homoerythromycins 1-4 were studied using a combination of X-ray crystallography, NMR spectroscopy and molecular modelling calculations. In the solid state 1 was found to exist as the two independent molecules with similar structures termed 3-endo-folded-out. In solution a significant conformational flexibility was noticed especially in the C2 to C5 region. The compounds 1 and 2 unlike 14-membered macrolides adopted the 3-endo-folded-out conformation while 3 and 4 existed in the classical folded-out conformation. TrNOESY and STD experiments showed that 1 and 2 bound to the Escherichia coli ribosome while 3 and 4, lacking the cladinose sugar, did not exhibit binding activities, this being in accordance with biochemical data. The bound conformations were found to be very similar to the free ones, some small differences were observed and discussed. The STD experiments provided evidence on binding epitopes. The structural parts of 1 and 2 in close contact with ribosome were similar, however the degree of saturation transfer was higher for 2. The differences between tr-NOE data and STD enhancements in 1 and 2 arouse as a consequence of structural changes upon binding and a closer proximity of 2 to the ribosome surface. An understanding of the molecular mechanisms involved in the interaction of macrolides with ribosomes can help in developing strategies aiming at design of potential inhibitors.

New Dinuclear Molybdenum(V) Complexes With β′‐Hydroxy‐β‐enaminones Containing a 4‐Hydroxy‐2‐pyrone Ring

New dinuclear molybdenum(V) complexes of the general formula [Mo2O4L2D2], were prepared by the reaction of [Mo2O3(acac)4] (acac = acetylacetonate ion) with β′-hydroxy-β-enaminones (L). All prepared complexes consist of Mo2O42+ cores coordinated by two ligands L via two donor oxygen atoms as in the analogous β-diketonates. The usual octahedral coordination around the molybdenum atoms is completed by the monodentate solvent molecules D (methanol, ethanol, or 2-propanol). All compounds were characterized by elemental analyses, IR, one- and two-dimensional NMR spectra, and thermal analysis, and some of them by X-ray crystallography (1a, 4a, 8b, and 9a). (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

In-line reaction monitoring of entacapone synthesis by Raman spectroscopy and multivariate analysis.

In-line Raman spectroscopy and multivariate analysis were used to monitor Knoevenagel condensation reaction, the final step in preparation of drug entacapone. By applying a fiber optical Raman probe immersed into a reaction vessel Raman spectra of the reaction mixture were recorded in situ during the entacapone synthesis in toluene, heptane and isobutyl acetate. Due to the complexity of the measured spectra, the obtained data were analyzed and interpreted by means of principal component analysis. It has been shown that progress of this reaction can be monitored in real-time and reaction end points can be determined in different solvents. The reaction was found to be the fastest in heptane due to the lower loss of the catalyst. For a comparison the reaction was independently monitored by off-line Raman spectroscopy and liquid chromatography which confirmed the results obtained in-line. The results presented here have shown that this in-line approach can be used as a fast, non destructive and reliable method to monitor the Knoevenagel reaction in real time. The knowledge gained in this study can further be exploited for the industrial process control.

Conformational analysis of oleandomycin and its 8-methylene-9-oxime derivative by NMR and molecular modelling

Conformations of the 14-membered macrolide antibiotic oleandomycin and its 8-methylene-9-oxime derivative were determined in various solvents. The experimental NMR data--coupling constants and NOE contacts--were compared with the results of molecular modelling--molecular mechanics calculations and molecular dynamics simulations. The conformational changes, on the right-hand side of the 14-membered ring, affected mostly the 3JH2,H3 values and NOE crosspeaks H3 or H4 to H11. Oleandomycin was found to be present predominantly in the C3-C5 folded-in conformations in DMSO-d6 solution, whereas in buffered D2O, acetone-d6 and CDCl3, there was a mixture of folded-in and folded-out conformational families. The predominant conformation of the 8-methylene-oleandomycin-9-oxime derivative in solution was a folded-out one although different amounts of folded-in conformation were also present depending on the solvent. Oleandrose and desosamine sugar moieties adopted the usual and expected chair conformation. The conformation around the glycosidic bonds, governing the relative orientation of sugars vs. the lactone ring, showed a certain flexibility within two conformationally close families. We believe that by combining the experimental NMR data and the molecular modelling techniques, as reported in this paper, we have made significant progress in understanding the conformational behaviour and properties of macrolides. Our belief is based on our own current studies on oleandomycins as well as on the previously reported results and best practices concerning other macrolides. A rational for macrolide conformational studies and advances in methodology has been suggested accordingly.

Vibrational coupling in trans-azobenzene and its isotopomers

Abstract Infrared (4000−400 cm−1) and Raman spectra (4000−100 cm−1) of six trans-azobenzene isotopomers, including the parent one, were recorded. Using mono and double 15N-labelled isotopomers, the assignment of the NN stretching was confirmed at 1439 cm−1 in the parent isotopomer. This vibration is strongly coupled with the phenyl mode 19b. In isotopomers with one and two perdeuterium-labelled phenyl groups the NN stretching shifts to higher wavenumbers, since this coupling is no longer effective.